Cannabidiol as an Intervention for Addictive Behaviors: A Systematic Review of the Evidence
US National Library of Medicine
Drug addiction is a chronically relapsing disorder characterized by the compulsive desire to use drugs and a loss of control over consumption. Cannabidiol (CBD), the second most abundant component of cannabis, is thought to modulate various neuronal circuits involved in drug addiction. The goal of this systematic review is to summarize the available preclinical and clinical data on the impact of CBD on addictive behaviors. MEDLINE and PubMed were searched for English and French language articles published before 2015. In all, 14 studies were found, 9 of which were conducted on animals and the remaining 5 on humans. A limited number of preclinical studies suggest that CBD may have therapeutic properties on opioid, cocaine, and psychostimulant addiction, and some preliminary data suggest that it may be beneficial in cannabis and tobacco addiction in humans. Further studies are clearly necessary to fully evaluate the potential of CBD as an intervention for addictive disorders.
Drug addiction is a chronically relapsing disorder characterized by the compulsive desire to seek and use drugs with impaired control over substance use despite negative consequences.1 In all, 162–324 million people between the ages of 15 and 64 have used an illicit substance worldwide in 2012, and approximately 183,000 deaths were thought to be drug related.2 In the past decade the advent of new technologies has allowed for a better understanding of the neural mechanisms involved in addictive disorders. The glutamatergic and dopaminergic systems have been found to play an important role in the reinforcing effects of drugs and prolonged risk of relapse.3–5 Moreover, the endocan-nabinoid system (ECBS) has been shown to influence the acquisition and maintenance of drug-seeking behaviors, through its role in reward and brain plasticity.6,7 Cannabinoid receptors have been studied in addiction-related processes, with special attention paid to cannabinoid type 1 (CB1) receptors. Other ionotropic cannabinoid receptors are also linked to neurophysiological functions in the ECBS, such as transient receptor potential receptors, including transient receptor vanilloid potential 1 (TRVP1), which binds the endogenous cannabinoid anandamide (AEA)5 (Supplementary Table 1 lists the abbreviations).
Among the compounds found to modulate the ECBS, Δ9-tetrahydrocannabinol (THC) has been widely studied since its discovery in the 1960s as the main component of cannabis extract. Its psychosis and anxiety-inducing addictive properties are well known.8,9 In contrast, cannabidiol (CBD), the second most abundant component of cannabis – less studied than THC – has been shown to have anxiolytic, anti psychotic, antidepressant, and neuroprotective properties.10–13 CBD acts on the ECBS as a weak inverse agonist on CB1 receptors, stimulates the TRVP1, and alters the hydrolysis of AEA by inhibiting fatty acid amine hydrolase.14–16 CBD has been shown to be an agonist of 5-HT1a serotoninergic receptors and to regulate stress response and compulsive behaviors.17 Moreover, CBD modulates allosterically μ and δ opioid receptors. The direct impact of CBD on glutamatergic neurotransmission is not known, but its protective effects on glutamate toxicity have been studied.18,19 Altogether, CBD has been associated with many neural circuits involved in the acquisition of addiction and subsequent drug-seeking behaviors, making it an interesting pharmacological candidate to treat substance-use disorders.
In past years, several researchers have studied the effects of CBD on physical and mental health, and a growing number have focused on the effects of CBD on addiction. The main objective of this review is to systematically examine the existing preclinical and clinical evidence on the effects of CBD on addictive behaviors.
Materials and Methods
The literature search was conducted in two electronic databases, MEDLINE and PubMed. The search was restricted to English and French-language articles before 2015. Both the databases were independently searched by two reviewers (MP and RC), and the titles and abstracts were sorted followed by careful reading of the complete articles when relevant. A first reviewer (MP) explored the databases by combining pertinent key words (eg, CBD + Addiction; detailed search strategy and key words can be obtained from the corresponding author), while the second reviewer (RC) explored all the articles found on both databases with the keyword “cannabidiol”. A third researcher (DJA) was consulted in the event of discrepancies occurring between the results of the two reviewers.
In order to be included, studies had to evaluate the outcomes of CBD on addictive behaviors, in any of the three phases of addiction (intoxication, withdrawal, and craving/relapse). Studies that focused on other outcomes only (anxiety, psychosis, pain, etc) were excluded. Studies evaluating the impact of CBD on addictive behaviors for all major types of substances of abuse (opioids, psychostimulants, cannabis, hallucinogens, sedatives, alcohol, tobacco, etc) have been included. Both studies on humans and animals were included. All types of study designs were included: clinical trials (randomized or not), observational, retrospective and prospective studies, and case reports.
Data extraction and analysis
When available, the following data were retrieved from the included studies: authors, publication year and journal, study design, characteristics of participants, sample size, objectives, type of intervention, results, and main limitations. According to a widely used conceptualization of addiction,20 the effects of CBD on addictive behaviors were classified in three distinct phases: the intoxication phase, when the drug produces positive rewarding experiences; the withdrawal phase, when the user experiences acute physical and psychological withdrawal symptoms, and the relapse phase, when the user experiences cravings and is at risk of drug-seeking behaviors after abstinence.
We identified 21 potentially eligible studies. After a careful review of articles, seven of those were excluded because their outcomes did not fit the purpose of this review or because they were duplicated (Supplementary Table 2 provides description of the excluded studies). Fourteen studies were included (Supplementary Fig. 1). Of those, nine were conducted on animals (seven experimental rat models, one experimental mice model, and two experimental models involving both rats and mice) and five on humans (one randomized placebo-controlled study, two crossover clinical studies, one randomized crossover clinical study, and one case report). Of the preclinical studies, five dealt with opioid, one with psychostimulant, one with opioid and psychostimulant, and two with cannabis addiction. Of the studies involving humans, three were related to cannabis, one to tobacco, and one to alcohol addiction (Supplementary Table 3 contains a detailed description of each study).
Included animal studies
Effects of CBD on opioid-related addictive behaviors
Studies were found on all three phases of opioid addiction. Using the intracranial self-stimulation (ICSS) paradigm (an operant conditioning method in which direct stimulation of brain areas by electrical or chemical means is rewarding), Katsidoni et al examined the effects of CBD on morphine’s brain reward function.21 They trained rats to ICSS, observed the impact of morphine (10 mg/kg) and CBD (5 mg/kg) on the ICSS threshold, and studied the involvement of 5-HT1A receptors in CBD’s action by adding a selective 5-HT1a receptor antagonist. They found that CBD inhibited the decrease of the ICSS threshold by morphine and thus its reward-facilitating effect, without influencing motor function. Moreover, the 5-HT1A receptor antagonist reversed CBD’s impact on the reward-facilitating effect of morphine.
Hine et al evaluated the effects of CBD on THC-induced attenuation of morphine abstinence syndrome.22After inducing morphine dependence in 33 rats and administrating tested agents (vehicle or CBD 10 mg/kg, followed by vehicle or THC 2 mg/kg), they induced withdrawal with naloxone and calculated an abstinence score based on specific signs (number of wet shakes or escapes, number of fecal boluses, presence of diarrhea, vocalization, abnormal posture, ear blanching, ptosis, chewing, or teeth chattering). The results showed that CBD alone did not influence the score, but reduced the number of fecal boluses, while increasing wet shakes. A synergic effect was revealed when CBD was combined to THC, which reduced the abstinence score to a greater extent than THC alone. Hine et al conducted another study, with the same objectives, doses, and methodology as the previous one.23 Again, they found that CBD potentiated the THC-induced reduction in abstinence score and raised the number of turnings. Bhargava also investigated the effects of cannabinoids on morphine withdrawal syndrome.24 Morphine dependence was induced in mice, various doses of cannabinoids were subsequently administered (including CBD 5, 10, 20 mg/kg), and withdrawal was precipitated with naloxone. The dose of naloxone required to provoke 50% of the mice to jump off of a platform was recorded during the withdrawal, as were defecation and rearing behaviors. CBD inhibited the naloxone withdrawal–induced jumping and reduced defecation and rearing behaviors. Chesher and Jackson assessed the response of THC, CBN, and CBD on quasi-morphine withdrawal syndrome (QMWS), elicited in 200 rats by administering a phosphodiesterase inhibitor followed by naloxone.25 They calculated withdrawal scores based on observed behavioral signs; the results showed that CBD at all doses (5, 20, 80 mg/kg) had no effect on QMWS.
More recently, Ren et al evaluated the impact of CBD on heroin addiction vulnerability using a drug self-administration (SA) rat model.26 Rats were trained to acquire a stable heroin SA intake, with each active level press resulting in drug injection and the activation of a stimulus white light. The effects of CBD were examined during the maintenance and extinction phases of SA and during cue-induced reinstatement. The results of this study indicate that CBD (one dose of 5 mg/kg or 5 mg/kg once daily for 3 days) specifically inhibited conditioned cue-induced heroin-seeking behavior for up to 2 weeks following the last administration without affecting motor function. On the other hand, CBD failed to influence drug-seeking behavior initiated by heroine prime. Moreover, neither the maintenance nor the extinction phase of SA was modified by CBD.
Overall, CBD was found to have an impact on the intoxication and relapse phase of opioid addiction. Data on its effect during the withdrawal phase remain conflicting and vary based on co-administration of other cannabinoids such as THC.
Effects of CBD on psychostimulant-addictive behaviors
Few studies examined the effects of CBD on the intoxication and relapse phases of psychostimulant addiction. In the previously cited study, Katsidoni et al also assessed the effect of CBD on cocaine’s brain reward function, with the same methodology and found that CBD (5 mg/kg) failed to inhibit a decrease in the ICSS threshold induced by cocaine (5 mg/kg).21
Parker et al assessed the impact of THC and CBD on cocaine- and amphetamine-induced conditioned place preference (CPP) in rats.27 After inducing CPP with the aforementioned drugs, THC (0.5 mg/kg), CBD (5 mg/kg), or a vehicle was administered, and the rats were given an extinction trial. They found that both cannabinoids potentiated the extinction of cocaine- and amphetamine-induced place preference learning and that this effect was not reversed by the administration of a CB1 receptors antagonist. These effects were not mediated by learning or retrieval alteration and CBD did not have hedonic properties on its own. Moreover, they also studied the effects of cannabinoids on the establishment of stimulant CPP. In that case, CBD showed no impact.
Thus, CBD does not appear to have an impact on stimulants’ rewarding effect, but one study suggests that it may influence addictive behaviors during the relapse phase.
Effects of CBD on cannabis-related addictive behaviors
Few studies have examined the effects of CBD administration on various outcomes during the intoxication and relapse phase of cannabis addiction. Vann et al assessed the effect of CBD on THC drug discrimination and CPP in rats and mice.28 After inducing THC drug discrimination and CPP, they tested several combinations of CBD and THC at different doses. The results showed that CBD alone did not produce a THC discrimination stimulus. THC and CBD (0.3, 3, 30 mg/kg) injection did not alter the drug discrimination at any dose, compared to THC alone. While high doses of THC produced a conditioned place aversion, no CPP or conditioned place aversion was recorded with CBD alone. In combination, low doses of CBD (1, 10 mg/kg) reversed the conditioned place aversion induced by THC (10 mg/kg). Klein et al also assessed the impact of CBD on THC place-conditioning effects and found a trend toward place preference induced by the combination of CBD and THC (both 10 mg/kg).29
While CBD does not appear to be reinforcing on its own, its impact on cannabis-related addictive behaviors in animal models remains unclear.
No animal study was found on hallucinogen-, sedative-, tobacco-, or alcohol-addictive behaviors.